An expedient synthesis of highly functionalized 1,3-dienes by employing cyclopropenes asC4units

Article abstract of DOI:10.1039/d1cc01254a

An efficient method has been described to synthesize dicarbonyl functionalized 1,3-dienes by cleaving the CC bond of enaminones with cyclopropenes in the presence of a rhodium catalyst. The acetate-substituted cyclopropenes are judiciously chosen as standardC₄units of 1,3-diene precursors. The reactions are believed to undergo a unique cutting and insertion process, involving a CC bond cleavage of the enaminone and insertion of a newC(sp²) source with the formation of two C-C single bonds. A broad range of substrates can be used to synthesize the corresponding 1,3-dienes under very mild reaction conditions, including low catalyst-loading, ambient temperature, and a neutral reaction solvent.

Full text of DOI:10.1039/d1cc01254a

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An expedient synthesis of highly functionalized
1,3-dienes by employing cyclopropenes as
C4 units†
Cite this: Chem. Commun., 2021,
57, 5710
Received 8th March 2021,
Accepted 30th April 2021
Chengzhou Jiang,a Jiamin Wu,a Jiabin Han,a Kai Chen,b Yang Qian,a
ab
Zhengyu Zhanga and Yaojia Jiang
*
DOI: 10.1039/d1cc01254a
rsc.li/chemcomm
An efficient method has been described to synthesize dicarbonyl units undergo coupling reactions; III. direct appendage of the
Q
functionalized 1,3-dienes by cleaving the C C bond of enaminones C4 unit of 1,3-diene with two carbonyl moieties. Although
with cyclopropenes in the presence of a rhodium catalyst. The strategies I and II are efficient, they might suffer from regio-
acetate-substituted cyclopropenes are judiciously chosen as stan- selectivity problems, harsh basic conditions, and tedious steps
dard C4 units of 1,3-diene precursors. The reactions are believed to in designing raw materials. Thus, we designed a cutting and
Q
undergo a unique cutting and insertion process, involving a C
C
insertion strategy III that employs substituted cyclopropenes as
bond cleavage of the enaminone and insertion of a new C(sp2) a new type of 1,3-diene C4 unit precursors.
source with the formation of two C–C single bonds. A broad range
Cyclopropenes are the smallest unsaturated carbocycles and
of substrates can be used to synthesize the corresponding exhibit high reactivity due to ring strains.4 In the presence of
1,3-dienes under very mild reaction conditions, including low transition metal catalysts, they can open the ring via the C–C
catalyst-loading, ambient temperature, and a neutral reaction single bond cleavage to generate vinyl carbene complexes,
solvent.
which participate in numerous transformations, including
X–H insertions (X = C, O, and N),5 cyclopropanations,6
1,3-Dienes are one of the most fundamental and ubiquitous cycloadditions,7 and coupling reactions.8 The obtained pro-
organic skeletons that are widely found in pharmaceuticals, ducts typically have an additional allyl functional group. In
natural products, and fine chemicals (Fig. 1).1 Significant contrast, employing cyclopropenes as 1,3-diene precursors is
efforts have been made to explore general and efficient syn- rarely reported.9 We envisioned that cyclopropene with a leav-
thetic methods for preparing 1,3-diene moieties.2 Larionov ing group, such as acetate, might serve as a unique 1,3-diene
et al. recently reported the synthesis of substituted conjugated unit. Enaminones have attracted wide attention in recent years
1,3-dienes via dienylation with sulfolenes as C4 units that form since their unique push–pull electronic reactivities of the
sulfonates in a palladium catalytic system.3 Inspired by these C–C double bond enable various transformations in
advances, we proposed to develop a general and straightfor- organic syntheses.10 Furthermore, dimethylamino-substituted
ward method to construct highly functionalized 1,3-dienes by enaminones are easily prepared from the condensation of
employing easily available C4 units. For instance, from the commercially available ketones and 1,1-dimethoxy-N,
retrosynthetic logic to the synthesis of dicarbonyl 1,3-dienes, N-dimethylmethanamine. Based on continuing interest in
there are three major synthetic protocols (Fig. 2): I. enaminone chemistry,11 herein, we described an expedient
1,4-Dicarbonyl compounds react with vinyl aldehydes through method to synthesize highly functionalized 1,3-dienes bearing
traditional carbonyl transformations; II. two well-polished C4 dicarbonyl groups through the cleavage of the CQC bond of
enaminones with cyclopropenes (Fig. 2, III).
a Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering,
College of Food Science and Light Industry, Nanjing Tech University,
Nanjing 211816, China. E-mail: iamyjjiang@njtech.edu.cn
b Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering,
Key Laboratory of Green Pesticide and Agricultural Bioengineering Ministry of
Education, Guizhou University, Huaxi, Guiyang 550025, China
† Electronic supplementary information (ESI) available. CCDC 2009014. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Fig. 1 Bioactive molecules carrying the 1,3-diene moiety.
d1cc01254a
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Table 1 Substrate scope of the enaminesab
Fig. 2 Representative reaction routes to 1,3-dienes.
In the beginning, we prepared (1-phenylcycloprop-2-en-1-yl)
methyl acetate 2a as a model substrate to react with enaminone
1a in the presence of different metal catalysts in dichloro-
methane (DCM) under nitrogen atmosphere (Table S1, see
ESI,† entries 1–3). The obtained results revealed that the
reaction failed to work with the copper catalyst (Table S1, entry 2),
while both silver (Table S1, entry 1) and rhodium catalysts
(Table S1, entry 3) successfully catalyzed the reaction to afford
a
Conditions: 1 (0.20 mmol), 2a (0.40 mmol), and Rh2(OAc)4 (1.0 mol%)
were stirred in 2.00 mL solution (HFIP : DCE = 9 : 1) under nitrogen
atmosphere. Isolated yields.
b
the conjugated 1,3-diene product 3aa albeit in low yields. The 2ae all reacted smoothly to provide the desired 1,3-diene 3aa
structure and geometry of 3aa were determined by 1H NMR, in lower yields (32%–65%) compared with acetate 2a.
13C NMR, and two-dimensional spectrum (NOESY). Then, the Methoxymethyl-substituted cyclopropene 2af reacted with
obvious solvent effects were observed (Table S1, entries 4–10). enaminone 1a to generate vinyl aldehyde 3aa0 in 61% yield
It showed that a more polar solvent could slightly increase with 1 : 1 of E/Z ratio.
the yields from 7% to 29% (Table S1, entries 4–8). The conver-
We first explored the scope of enamine substrates 1 to react
sion of the reaction was improved significantly to 68% with (1-phenylcycloprop-2-en-1-yl)methyl acetate 2a under the
yield in hexafluoroisopropanol (HFIP) (Table S1, entry 9). optimized catalytic system (Table 1). In general, numerous
The yield was further increased to 84% by employing 1, substituted enaminones and enaminolates reacted smoothly
2-dichloroethane (DCE) as the co-solvent (Table S1, entry 10). to give 1,3-diene-4-aldehydes in moderate to good yields with
Then, we turned our attention to different rhodium catalysts sole E isomer. Aryl halide (F, Cl, Br, and I) enaminones also
(Table S1, entries 11–13), and found that Rh2(OAc)4 still gave successfully underwent the reaction to generate the desired
the best result compared to Rh2(TFA)4, Rh2(Oct)4, and products in promising yields (3ba–3ga). The yields of ortho- and
Rh2(esp)2. Finally, the optimized conditions are as follows: meta- aryl chlorides decreased (36% and 45%), which may be
enaminone 1a (0.20 mmol), cyclopropene 2a (0.40 mmol), due to the steric effects (3ca–3da). Aryl halides (Cl, Br, and I) are
and Rh2(OAc)4 (1.0 mol%) were stirred in a mixed solvent general and important starting materials in transition-metal
system of HFIP and DCE at room temperature under nitrogen promoted name reactions such as Mizoroki–Heck reaction and
atmosphere to give 84% isolated yield (Table S1, entry 10).
Suzuki–Miyaura reaction, which allow the obtained 1,3-diene-4-
Then, cyclopropenes 2 with different leaving groups were aldehydes for further functionalizations.12 Then, the electronic
further examined under the optimized conditions to study how effects in the reactions were studied, and it was found that
these leaving groups influence the reaction efficiency (Table S2, electron-donating substituents (3ha–3ia) gave higher yields
see ESI†). The results showed that cyclopropene with a free (80% and 71%) than the electron-withdrawing substrate (3ja,
hydroxyl group 2aa was quite stable under the rhodium cataly- 51%). Polycyclic aromatic-functionalized enaminones, such as
tic system, and the starting material 1a was recovered comple- naphthyl and phenanthryl groups, reacted smoothly to afford
tely. Trifluoroacetate-substituted cyclopropene 2ab, on the the dicarbonyl 1,3-dienes in moderate yields (3ka–3la). Hetero-
other hand, was too reactive and decomposed with unidentified cyclic substrates, including thienyl and furyl, also reacted well
complex mixtures. Pivalate 2ac, benzoate 2ad, and picolinate and gave the corresponding products in 71% and 77% yields,
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respectively (3ma and 3na). Cinnamaldehyde-derived enami-
none was then examined. The result revealed that only the
double bond of the enamine moiety took part in the reaction,
and the conjugated C–C double bond (3oa) was retained. Then,
the reactions of a series of alkyl-substituted enaminones were
carried out under standard conditions to give the 1,3-dienes in
moderate to good yields (3pa–3ua). The following steric effects
were observed: the enaminones with primary, secondary,
tertiary, and quaternary alkyl substitutions gave the desired
products in a downward trend of yields from 68% to 42%
(3pa–3sa). Furthermore, cyclic alkyl even ring-strained cyclo-
propyl substitutions also survived under the catalytic condi-
tions (3ta–3ua). Enaminolates were then examined under the
standard reaction conditions. The dicarbonyl functionalized
1,3-dienes were obtained in 52% and 41% yields, respectively
(3va–3wa).
Next, the scope of the substituted cyclopropenes was exam-
ined in the same rhodium catalytic system (Table 2). On the
whole, cyclopropene-bearing aryl groups reacted and con-
structed the desired functionalized 1,3-dienes in promising
yields. Aryl halides including F, Cl, and Br could react success-
fully, and the corresponding products can be obtained in 56%
to 82% yields (3ab–3af). Then, the electronic effects of the
reactions were observed, and the electron-rich substituents
(3ag–3ah) were more effective than the electron-withdrawing
substituents (3ai). The naphthyl-substituted group also sur-
vived under the mild reaction conditions and afforded the
corresponding 1,3-dienes in 62% yield (3aj). The structure
and geometry of 3ak were analyzed and verified using single
crystal X-ray data (CCDC 2009014).
Scheme 1 Mechanism study.
protonation/deuteration with 2.0 equivalents of D2O might
not be able to compete with the more acidic HFIP on the
solvent-scale. When H218O was subjected to the reaction, 18O
was detected in the desired product 3aa-II in 72% (Scheme 1c).
These results indicate that the oxygen of the formyl group was
generated from either the trace amount of water or in situ
generated water.
Based on the obtained results, we proposed a plausible
reaction pathway as described in Scheme 2. Initially, cyclopro-
pene 2a undergoes a ring-opening process to generate rhodium
carbenoid-A due to the ring-strain.13 The intermediate A is
undergoes cyclopropanation with enaminone 1a to afford amino-
cyclopropane intermediate B. Notably, the analogue of amino-
cyclopropane B could be isolated and reliably determined
in the previous work.11b The push–pull electronic effect of
amino and carbonyl groups may promote the regioselective
C–C single bond cleavage and consequently hydrolysis to C.11c
The complex C on further deamination affords the vinyl
1,4-ketaldehyde intermediate D. Finally, the intermediate D
undergoes HOAc elimination by Me2NH promotion to generate
3aa as the only E isomer due to thermodynamic stability.14
The reaction was further carried out with a scale-up to
6 mmol of enaminone 1a to demonstrate the synthetic utility of this
method (Scheme 3). To our delight, the reaction worked efficiently
and gave the corresponding product 3aa in 1.17 gram (71%)
Several control experiments were then investigated to better
understand the reaction mechanism (Scheme 1). Isotopic label-
ling experiments including D2O and (CF3)2CDOD were studied.
The D-labelling products were found only in the methylene C–H
bonds with (CF3)2CDOD (Scheme 1a and b). It seems that
Table 2 Substrate scope of cyclopropenesab
a
Conditions: 1 (0.20 mmol), 2a (0.40 mmol) and Rh2(OAc)4 (1.0 mol%)
were stirred in 2.00 mL solution (HFIP : DCE = 9 : 1) under nitrogen
atmosphere. Isolated yields.
b
Scheme 2 Proposed mechanism.
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Conflicts of interest
The authors declare no competing financial interest.
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